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Expression of inducible NOS is indispensable for the antiproliferative and proapoptotic effect of imatinib in BCR-ABL positive cells.
Abstract Chronic myeloid leukemia (CML) is characterized by constitutive BCR-ABL kinase activity, an aggressive proliferation of immature cells, and reduced differentiation. Targeting tyrosine kinase activity of BCR-ABL with imatinib is an effective therapy for the newly diagnosed CML patients; however, 20%-30% of the patients initially treated with imatinib eventually experience treatment failure. Therefore, early identification of these patients is of high clinical relevance. In the present study, we by undertaking a direct comparison of inducible NOS (iNOS) status in neutrophils from healthy volunteers, newly d...
Source: Journal of Leukocyte Biology - February 2, 2021 Category: Hematology Authors: Singh AK, Awasthi D, Dubey M, Nagarkoti S, Chandra T, Barthwal MK, Tripathi AK, Dikshit M Tags: J Leukoc Biol Source Type: research

PKM2 Mediates Chronic Myeloid Leukemia Imatinib Resistance By Regulating Glycolysis Energy Metabolism
Conclusion: Pyruvate kinase M2 (PKM2) acts as an important rate-limiting enzyme in the aerobic glycolytic pathway, and mediates abnormal metabolic pathways which promote tumor cell proliferation, invasion and drug resistance. Compared to the TKI-sensitive primary cell and cell line, PKM2 was increased in the TKI-resistant primary cell and cell line and related to glycolytic level. PKM2 inhibitor can inhibit CML cells growth, induce cell apoptosis, and combined with IM at a low dose can exhibited a synergistic anti-leukemia effect on TKI-resistant cells. Low dose PKM2 inhibitor combined with IM can enhance targeted killing ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Tong, L., Xu, N., Zhou, X., Huang, J., wan-Er, W., Chen, C., Liang, L., Liu, Q., Xiaoli, L. Tags: 631. Chronic Myeloid Leukemia: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research

Aurora Kinase a/MDM2-Mediated SETD2 Loss of Function in Chronic Myeloid Leukemia Patients in Blast Crisis Induces Genetic Instability and Can be Therapeutically Targeted
In conclusion, phosphorylation by Aurora Kinase A and ubiquitination by MDM2 contribute to SETD2 non-genomic loss of function in advanced-phase CML. Loss of SETD2/H3K36me3 is associated with increased DNA damage and impaired HR repair. Restoring physiological H3K36me3 levels may help improve the outcome of this critical subset of pts.Acknowledgments: study supported by AIRC (project code 16996) and AIL (Associazione Italiana contro le Leucemia, Linfomi e Mieloma).Figure 1.DisclosuresCastagnetti: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consulta...
Source: Blood - November 21, 2018 Category: Hematology Authors: Mancini, M., De Santis, S., Monaldi, C., Bavaro, L., Martelli, M., Castagnetti, F., Gugliotta, G., Rosti, G., Fontana, M. C., Dan, E., Sinigaglia, B., Iurlo, A., Orofino, N., Abruzzese, E., Salvucci, M., Pregno, P., Gozzini, A., Crugnola, M., Albano, F., Tags: 631. Chronic Myeloid Leukemia: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research

Concomitant Targeting of FLT3 and BTK with CG'806 Overcomes FLT3-Inhibitor Resistance through Inhibition of Autophagy
Fms-like tyrosine kinase 3 (FLT3)-targeted therapy represents an important paradigm in the management of patients with highly aggressive FLT3 mutated acute myeloid leukemia (AML). However, clinical efficacy is usually transient and followed by emergence of resistance to FLT3-inhibitors (Borthakur et al., 2011; Cortes et al., 2013; Zhang et al., 2008). Such resistance often results from acquired mutations of TKD, which are frequently identified in D835, Y842 and F691 residues (Smith et al., 2015; Smith et al., 2012; Zhang et al., 2014). It was reported that the FLT3-ITD-targeting drug sorafenib can induce autophagy in human...
Source: Blood - November 21, 2018 Category: Hematology Authors: Zhang, W., Yu, G., Zhang, H., Ly, C., Yuan, B., Ruvolo, V., Piya, S., Bhattacharya, S., Zhang, Q., Borthakur, G., Battula, V. L., Konopleva, M. Y., Rice, W. G., Andreeff, M. Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster II Source Type: research

Proliferation inhibition and apoptosis induction of imatinib-resistant chronic myeloid leukemia cells via PPP2R5C down-regulation
In conclusion, the suppression of PPP2R5C by RNA interference could inhibit proliferation and effectively induce apoptosis in CML cells that were either imatinib sensitive or resistant. Down-regulating PPP2R5C gene expression might be considered as a new therapeutic target strategy for CML, particularly for imatinib-resistant CML.
Source: Journal of Hematology and Oncology - September 3, 2013 Category: Hematology Authors: Qi ShenSichu LiuYu ChenLijian YangShaohua ChenXiuli WuBo LiYuhong LuKanger ZhuYangqiu Li Source Type: research

The role of TC-PTP (PTPN2) in modulating sensitivity to imatinib and interferon-α in CML cell line, KT-1 cells
Abstract: T-cell protein tyrosine phosphatase (TC-PTP, also known as PTPN2) is a negative regulator of the JAK/STAT pathway. STAT5 is activated by BCR-ABL kinase and STAT1 is an important transcription factor for interferon (IFN)-α-induced signaling in chronic myeloid leukemia (CML). We used siRNA to delete TC-PTP in the CML cell line, KT-1, and examined changes in the sensitivity to imatinib and IFN-α. Suppression of TC-PTP induced activation of STAT5, leading to imatinib resistance, while prolonged phosphorylation of STAT1 was induced by IFN-α, triggering cell death in KT-1 cells. These findings suggest that TC-PTP mo...
Source: Leukemia Research - June 6, 2013 Category: Hematology Authors: Yuriko Nishiyama-Fujita, Takatsune Shimizu, Morihiko Sagawa, Hideo Uchida, Masahiro Kizaki Tags: Laboratory Studies Source Type: research

Induction of autophagy by imatinib sequesters Bcr‐Abl in autophagosomes and down‐regulates Bcr‐Abl protein
In this study, we show that following Imatinib treatment, Bcr‐Abl is sequestered into vesicular structures that co‐localize with the autophagy marker LC3 or GABARAP. This association is inhibited by siRNA mediated knockdown of autophagy regulators (Beclin 1/ATG7). Pharmacological inhibition of autophagy also reduced Bcr‐Abl/LC3 co‐localization in both K562 and CML patient cells. Bcr‐Abl protein expression was reduced with Imatinib treatment. Inhibition of both autophagy and proteasome activity in Imatinib treated cells was required to restore Bcr‐Abl protein levels to those of untreated cells. This ability to d...
Source: American Journal of Hematology - February 26, 2013 Category: Hematology Authors: Baukje M. Elzinga, Michelle J. Nyhan, Lisa C. Crowley, Tracey R. O'Donovan, Mary R. Cahill, Sharon L. McKenna Tags: Research Article Source Type: research